PATH-40. “DE NOVO REPLICATION REPAIR DEFICIENT GLIOBLASTOMA, IDH-WILDTYPE” IS A DISTINCT GLIOBLASTOMA SUBTYPE IN ADULTS THAT MAY BENEFIT FROM IMMUNE CHECKPOINT BLOCKADE

Abstract

Abstract Glioblastoma is clinically and molecularly heterogeneous, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a subgroup (2%, 8/459) defined by somatic hypermutation and DNA replication repair deficiency due to mismatch repair gene inactivation and/or proofreading domain mutation in the DNA polymerase POLE. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining wildtype allele, consistent Lynch syndrome-associated glioblastomas. All tumors were hypermutated ( >20 somatic nonsynonymous mutations/Mb), while the three tumors with POLE mutations were “ultrahypermutated” with >150 mutations/Mb. The median age at diagnosis was 52 years (range 27-78), compared with median age of 63 years for the other 451 patients with conventional glioblastoma. All tumors were diffuse astrocytic gliomas of the giant cell histologic subtype. They lacked EGFR amplification and only rarely had TERT promoter mutation (1/8), CDKN2A homozygous deletion (1/8), or the combination of trisomy 7 and monosomy 10 (1/8). Instead, they harbored frequent inactivating mutations in the TP53, NF1, PTEN, ATRX, and SETD2 genes ( >50% each) and recurrent activating mutations in PDGFRA (4/8). DNA methylation profiling revealed they did not align with known glioblastoma methylation classes, but instead mostly classified as “Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A (novel)”. Some patients were treated with immune checkpoint blockade (nivolumab or pembrolizumab) and survived over three years. The median overall survival for the cohort was 37.4 months (95% CI: 22-not reached), compared to 15.4 months (95% CI: 14.7-17.9) for the other 451 patients. We speculate that “de novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype that may benefit from prospective identification and treatment with immune checkpoint blockade.